The present invention relates to an improved process for oxidizing 3-hydroxy-methyl-cephem derivatives to the corresponding 3-formyl-cephem derivatives. In particular this oxidation process is for the preparation of 7-[2-(5-amino-[1,2,4]thia-diazol-3-yl)-2-hydroxyimino-acetylamino]-3-formyl-8-oxo-5-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid derivatives of formula (I) using a combination of a hypervalent iodine oxidizing agent of the type 10-I-3 such as bis(acetoxy)iodo-benzene (BAIB) and a catalyst such as 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). These compounds of formula (I) are intermediates in the synthesis of ceftobiprole.

Compounds of formula (I) and methods for preparing these compounds have been disclosed in WO-01/90111. WO-01/90111 also discloses a process for the preparation of ceftobiprole. Other methods for the preparation of ceftobiprole are disclosed in WO-99/65920 and Drugs of the Future, 30(1), p. 11-22 (2005).
Ceftobiprole is a parenterally administered cephalosporin with high affinity for most penicillin-binding proteins, including the mecA product penicillin binding protein (PBP) 2a, rendering it active against methicillin-resistant Staphylococcus aureus (MRSA). Ceftobiprole shows broad-spectrum activity against relevant resistant Gram-positive and Gram-negative pathogens in vitro and has a low liability to induce resistance. It is administered in vivo as a water soluble prodrug, ceftobiprole medocaril, which is rapidly cleaved in plasma to form ceftobiprole, diacetyl and CO2. The chemical structure of ceftobiprole and ceftobiprole medocaril are shown below.

WO-01/90111 discloses two oxidation procedures (Example 2 on page 16) for oxidizing 3-hydroxy-methyl-cephem derivatives of formula (II) to the corresponding 3-formyl-cephem derivatives of formula (I):

The first oxidation procedure disclosed in WO-01/90111 uses a mixture of an inorganic hypohalite such as sodium hypochlorite and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) whereby the reaction mixture is a two-phase mixture of water and dichloromethane that is vigorously stirred. Substituent R1 is a hydroxy protecting group (triphenylmethyl group) and R2 is a carboxylic acid protecting group, (diphenylmethyl). The reported yield is 74%.
The second oxidation procedure disclosed in WO-01/90111 uses MnO2 as the oxidizing agent suspended in a mixture of tetrahydrofuran and dichloromethane. The reported yield is 52%.
In general the present invention concerns the oxidation of a primary alcohol to an aldehyde using an oxidizing agent. A number of art known oxidizing agents are known such as Jones reagent (chromic acid and sulfuric acid in water), Collins reagent (dipyridine Cr(VI) oxide), Dess-Martin periodinane, pyridinium chlorochromate (PCC), pyridinium dichromate (PDC), MnO2, o-iodoxy benzoic acid (IBX), methyl-2-iodoxy benzoate, isopropyl-2-iodoxy benzoate,trichloro isocyanuric acid, and a combination of TEMPO with an inorganic hypochlorite. The selection of the most suitable oxidizing agent is a cumbersome process wherein issues such as over-oxidation to a carboxylic acid, yield, impurities, cost, reaction time, scale-up possibilities, and the like have to be evaluated in order to achieve the best results.
The oxidation procedures to convert 3-hydroxymethyl-cephem derivatives of formula (II) to the corresponding 3-formyl-cephem derivatives of formula (I) as disclosed in WO-01/90111 (Example 2 on page 16) have the following disadvantages:                low yield: 52% when MnO2 is used        low yield: 74% when a combination of sodium hypochlorite and TEMPO as oxidizing agent is used        sodium hypochlorite needs to be carefully dosed in a continuous way to minimise over-oxidation (formation of S-oxides)        heterogeneous two-phase system of water and dichloromethane that needs to be stirred vigorously        large volume of solvent is needed: about 7.6 litre/mol.        